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Scratching Counteracts IL-13 Signaling by Upregulating the Decoy Receptor IL-13Rα2 in Keratinocytes

1
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
2
Department of Dermatology, National Dermatology Center of Mongolia, Ulaanbaatar 14171, Mongolia
3
Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
4
Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(13), 3324; https://doi.org/10.3390/ijms20133324
Received: 26 June 2019 / Revised: 3 July 2019 / Accepted: 4 July 2019 / Published: 6 July 2019
(This article belongs to the Special Issue Therapy and Prevention of Atopic Dermatitis and Psoriasis)
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Abstract

The vicious itch–scratch cycle is a cardinal feature of atopic dermatitis (AD), in which IL-13 signaling plays a dominant role. Keratinocytes express two receptors: The heterodimeric IL-4Rα/IL-13Rα1 and IL-13Rα2. The former one transduces a functional IL-13 signal, whereas the latter IL-13Rα2 works as a nonfunctional decoy receptor. To examine whether scratch injury affects the expression of IL-4Rα, IL-13Rα1, and IL-13Rα2, we scratched confluent keratinocyte sheets and examined the expression of three IL-13 receptors using quantitative real-time PCR (qRT-PCR) and immunofluorescence techniques. Scratch injuries significantly upregulated the expression of IL13RA2 in a scratch line number-dependent manner. Scratch-induced IL13RA2 upregulation was synergistically enhanced in the simultaneous presence of IL-13. In contrast, scratch injuries did not alter the expression of IL4R and IL13RA1, even in the presence of IL-13. Scratch-induced IL13RA2 expression was dependent on ERK1/2 and p38 MAPK signals. The expression of IL-13Rα2 protein was indeed augmented in the scratch edge area and was also overexpressed in lichenified lesional AD skin. IL-13 inhibited the expression of involucrin, an important epidermal terminal differentiation molecule. IL-13-mediated downregulation of involucrin was attenuated in IL-13Rα2-overexpressed keratinocytes, confirming the decoy function of IL-13Rα2. Our findings indicate that scratching upregulates the expression of the IL-13 decoy receptor IL-13Rα2 and counteracts IL-13 signaling. View Full-Text
Keywords: scratch injury; IL-13Rα2; keratinocyte; IL-13; atopic dermatitis; IL-4Rα; IL-13Rα1; involucrin scratch injury; IL-13Rα2; keratinocyte; IL-13; atopic dermatitis; IL-4Rα; IL-13Rα1; involucrin
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Ulzii, D.; Kido-Nakahara, M.; Nakahara, T.; Tsuji, G.; Furue, K.; Hashimoto-Hachiya, A.; Furue, M. Scratching Counteracts IL-13 Signaling by Upregulating the Decoy Receptor IL-13Rα2 in Keratinocytes. Int. J. Mol. Sci. 2019, 20, 3324.

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